Our concepts about the cortical control of movement have undergone a dramatic evolution. In the past, the primary motor cortex (M1) was viewed as the sole source of descending command signals to the spinal cord. Other cortical areas and subcortical structures like the basal ganglia and cerebellum were thought to influence the control of movement mainly through their connections with M1. We now know that the frontal lobe contains 6 premotor areas. Each of these cortical areas projects not only to M1, but also directly to the spinal cord. As a consequence, the central commands for movement may originate not only from M1, but also from each of the premotor areas. We now propose to examine four fundamental questions about the organization of the premotor areas: (1) Although all of the premotor areas project to the spinal cord, which of the premotor areas are major sources of descending commands to motoneurons? (2) We have found that output neurons within two premotor areas are connected to motoneurons that control eye muscles. Do these premotor areas create a neural interface between the oculomotor and skeletomotor systems? (3) We have also discovered that output neurons in M1 and in the premotor areas are connected to neurons that control the sympathetic nervous system. Do these motor areas create a neural interface between the visceromotor and skeletomotor systems? (4) Approximately 25% of the corticospinal efferents from the frontal lobe originate from the cingulate motor areas. What is the organization of inputs to these areas from the basal ganglia, cerebellum and spinal cord? Each of these questions will be answered in a separate experiment. However, each question requires a technical approach that is capable of unraveling neural connections within complex, multi-synaptic networks. Thus, we will use transneuronal transport of neurotropic viruses in these experiments because this technique is uniquely capable of defining circuits of synaptically-linked neurons. The results from the proposed studies are likely to have broad implications for concepts about the function of the cortical motor areas in normal movement, their involvement in the motor and non-motor symptoms of movement disorders like Parkinson's disease and their role in the recovery of motor function following brain or spinal cord injury. PUBLIC HEALTH RELEVANCE: The results from the proposed studies are likely to provide important new insights into how the cerebral cortex normally generates and controls movement. The results also are likely have broad implications for concepts about how to treat the motor and non-motor symptoms of movement disorders like Parkinson's disease, as well as how to promote the recovery of motor function following brain or spinal cord injury.